Ch' 14' Lipid Metabolism

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Ch. 14. Lipid Metabolism

• Atherosclerosis
• Lipoprotein
• LDL
• VLDL
• HDL
• Table 14-1

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Figure 14.01 An atheroscleroptic plaque blocking
the lumen of an artery.
Figure 14.02 Theoretical model of Lipoprotein
structure.
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Figure 14.03 Lippoprotein function.
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Figure 14.04 Lipid metabolism in context.
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1. Fatty acid oxidation

• Source of metabolic free energy
• Dietary triacylglycerol the primary source of
  fatty acids
• ? triacylglycerol (tissue)? glycerol 3 fatty
  acyl groups (by lipoprotein lipase)
• ? triacylglycerol (adipose tissue)? glycerol
  3 fatty acyl groups (by hormone-sensitive lipase)
  fatty acids bound to albumin and mobilized
• ? occur extracellularly
• ? free FA very low in body

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Fatty acids are activated before they are
degraded

• Activation of FA by acyl-CoA synthetas
• ?FA ATP ? acyladenylate ( PPi) ? acyl-CoA
  (AMP)
• ?Free energy change near zero, but ppi
  hydrolysis _____________
• ?occurs in cytosol, but FA oxidation occurs in
  mitochondria
• ? shuttle system using small carnitine (figure
  14-5)

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Figure 14.05 The carnitine shuttle system.
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Beta oxidation a pathway with four reactions

• Generation of acetyl-CoA and an acyl-CoA
  shortened by two carbons
• A spiral pathway Each round consisting of 4
  enzymes (specialized for chain length)
• oxidation occurs at the beta position
• Figure 14-6

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Figure 14.06 The reactions of ß oxidation.
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Energy yield of Beta oxidation

• beta oxidation major source of cellular free
  energy (especially during fast)
• Each round 1 QH2, 1 NADH, 1 acetyl-CoA(3 NADH, 1
  QH2, 1 GTP)? 17 ATP

Oxidation of unsaturated fatty acids

• Linoleate contains two cis double bonds ? How to
  remove the double bonds?
• ? enoyl-CoA isomerase
• ? NADPH-dependent dienoyl-CoA reductase
• ? energy loss

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Oxidation of odd-chain fatty acids

• Final product of odd-numbered fatty acid
  oxidation propionyl-CoA
• Catabolism of propionyl-CoA fig 14-7
• Methymalonyl-CoA mutase use Vitamin
  B12(cobalamin) as cofactor

Figure 14.07 Catabolism of propionyl-CoA.
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Figure 14.08 The cobalamin-derived cofactor.
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Fatty acid oxidation in peroxisomes

• Place of FA oxidation mitochondria (major),
  peroxisome (minor)
• Peroxisomes
• ? single membrane-bound compartments
• ? contain a variety of degradative and
  biosynthetic enzymes
• ? The ifrst step of FA oxidation differ from
  mitochondrias method,
• Acyl-CoA ? Enoyl-CoA
• (by acyl-CoA oxidase with FAD reduction and
  H2O2 production)
• ? H2O2 break down by peroxisome catalase

? a chain-shortening system specific for
very-long FA (gt20 C), low binding affinity for
short-chain FA ? degrades some branched-chain FA
such as phytanate (Refsums disease) ? fatal
disease from deficient peroxisomal enzymes
Figure 14.09 Peroxisomes.
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2. Fatty acid synthesis

• Thermodynamic consideration
• Comparison of oxidation and synthesis

• ? Place
• ? cofactors
• attachment
• electron carrier
• ? energy consumption

Figure 14.10 Acyl carrier protein and coenzyme A.
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The source of cytosolic acetyl-CoA

• Citrate mediates transfer of acetyl-CoA from
  mitochondria to the cytosol
• Citrate synthase ATP-citrate lyase
• Fig 14-11

Figure 14.11 The citrate transport system.
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Acetyl-CoA carboxylase catalyzes the first step
of fatty acid synthesis

• carboxylation of acetyl-CoA the first step of FA
  synthesis, ATP-dependent reaction catalyzed by
  Acetyl-CoA carboxylase, a rate controlling step
  of FA synthesis pathway
• Involves C3 intermediate
• ? activation of CO2
• Biotin HCO3- ATP ? Biotin-COO- ADP
  Pi
• ? transfering the carboxylate group
• Biotin-COO- Acetyl-CoA ? malonyl-CoA
  Biotin
• malonyl-CoA the donor of 2 C unit for FA
  synhtesis

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The reactions of fatty acid synthase

• 530 kD multifunctional enzymes two identical
  polypeptides
• 2 NADPH provided from pentose phosphate pathway
• 1 palmitate synthesis 7ATP 14 NADPH (total
  49ATP)less E than synthesis
• Mammalian FA synthase packaging several enzyme
  activities into one functional protein

Electron micrograph of fatty acid synthase.
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Fatty acid synthesis.
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Other enzymes elongate and desaturate newly
synthesized fatty acids

• Elongation C22 C24 FA (synthesized from C16 FA
  by elongase), occur in either the ER or
  mitochondria
• Desaturation occur in the ER (most cis form.
  Trans FA?)
• Elongation can follow desaturation, resulting in
  various unsaturated FA with different C numbers
• Mammals cant introduce beyond C9, must obtain
  linoleate and linolenate (precursors of
  arachidonate) from diet.

Figure 14.14 Synthesis of arachidonate.
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Regulation of fatty acid synthesis

• Under condition of abundant metabolic fuel
  catabolic product of carbohydrate, aa ?FA
  synthesis ? triacylglycerol synthesis ( stored)
• Rate is regulated by acetyl-CoA carboxylase
  (inhibitor_______________, activator
  _____________)
• Malonyl-CoA critical for preventing wasteful
  simultaneous activity of FA synthesis and
  oxidation (fig 14-15)
• Inhibitors of FA synthesis triclosan,
  anti-obesity and anti-cancer activity?

Some control mechanism in fatty acid metabolism.
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Ketogenesis

• Under condition of prolonged fast
  triacylglycerol ? FA (major source of energy)
• Brain dont use FA as energy source,
  gluconeogenesis occurred
• Ketogenesis ketone body formation in liver
• Ketone body soluble and small, pass through to
  CNS, consumed in brain
• Ketoacidosis
• Oxidation of keotone bodies used by other
  tissues after conversion to acetyl-CoA

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Figure 14.16 Ketogenesis.
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Ketogenesis

• Under condition of prolonged fast
  triacylglycerol ? FA (major source of energy)
• Brain dont use FA as energy source,
  gluconeogenesis occurred
• Ketogenesis ketone body formation in liver
• Ketone body soluble and small, pass through to
  CNS, consumed in brain
• Ketoacidosis
• Oxidation of keotone bodies used by other
  tissues after conversion to acetyl-CoA

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Figure 14.17 Catabolism of ketone bodies.
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3. Synthesis of other lipids
FA i) a structural components of other lipids
ii) precursors of specialized
lipids Triacylglycerol synthesis - Attach FA
groups to a glycerol backbone - Acyl-CoA
activated FA - Acyltransferase not specific for
chain length or unsaturation - can be stored in
adipocytes as droplet surrounded by phopholipids
Figure 14.19 Triaclyglycerol synthesis.
Electron micrograph of an adipocyte.
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• Phospholipid synthesis
• - CTP used for activation of acyl or head group
  of phospholipid synthesis
• - Cellular membrane
• inserting lipid and proteins into preexsiting
  membranes (mainly ER)
• ? Remodeled by phospholipases and
  acyltransferases

Synthesis of phosphatidylethanolamine and
phosphatidylcholine.
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Figure 14.21 Phoshatidylinositol synthesis.
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Lipid as biological signals Membrane lipids
precursors of molecules with signaling
functions Arachidonate a C20 FA with four double
bonds, used for synthesis of eicosanoids Eicosano
ids Prostaglandins, cyclooxigenase (COX),
aspirin (Box 14-C)
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• Cholesterol synthesis
• From acetyl-CoA to mevalonate fig 14-22
• From mevalonate to isopentenyl pyrophosphate
• Condensation of 6 isoprene units to squalene
  (C30)
• Conversion of squalene to cholesterol total 21
  reactions, fig 14-23
• Rate limiting step conversion of HMG-CoA to
  mevalonate
• ? HMG-CoA reductase
• ? synthetic inhibitors
• ? side effect?

Figure 14.24 Some statins.
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Figure 14.22 The first steps of cholesterol
biosynthesis.
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Figure 14.23 Structure of a squalene, a precursor
of cholesterol.
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• The Fate of cholesterol
• 1)
• 2)
• 3)
• 4) A precursor of bile acid (the only route for
  cholesterol disposal)
• LDL source of cholesterol, receptor and
  endocytosis
• Familial hypercholesterolemia
• HDL essential to remove excess cholesterol from
  cells
• Regulation of cholesterol synthesis (Cells
  dont degrade cholesterol!)
• ?
• ?
• ?

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4. Summary of Lipid Metabolism
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Problem 14.05
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Problem 14.08
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Problem 14.21
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Problem 14.30
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Problem 14.30a
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Problem 14.30c
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Problem 14.30d
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Problem 14.31
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Problem 14.31